Process for preparing 9alpha-fluoro steroids



PROCESS FOR PREPARING 9u-FLUOR0 STEROIDS Robert P. Graber, Elizabeth, and C. Stewart Snoddy, Jr.,

Plainfield, N.J., assignors to Merck 8: Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Application February 3, 1955 Serial No. 486,022

4 Claims. (Cl. 260-39745) This invention relates to an improved process for preparing 9lx-fiuoro-steroids.

One general method applicable for the synthesis of 9afluoro-4-pregnene-l 15,17a,21-triol-3 ,Z-O-dione 2 l-acetate is the reported procedure in J.A.C.S. vol. 76, pages 1455-6 (1954). In this procedure, disclosed by Fried et al., a solution of 95,115-oxido-4 pregnene-17 ,21-diol-3,20-

S e P -e ro "ice dione 21-acetate in anhydrous, chloroform free of ethanol is treated with anhydroushydrogen fluoride under anhydrous conditions to obtain 9a-fluoro-4-pregnene415,17a, 21-triol-3,20-dione ZI-acetate in about 50% yield. This reaction can be chemically represented, as follows:

0 ong-o-ii-on,

L 03 o i Anhydrous o= HF 'One of the primary disadvantages of this method is that it is carried out under anhydrous conditions which are objectionable in commercial manufacturing opera tions. Moreover the handling of large amounts of anhydrous hydrogen fluoride is extremely hazardous and difiicult, and especially so when used industrially. The reaction requires the strict control of the concentration of hydrogen fluoride which necessitates laborious and hazardous titrations. In addition the preparation and storage of alcohol-free chloroform is difficult and undesirable. In view of these difiiculties, the Fried et a1. method is looked on as a laboratory procedure and not as a process EYEF 11 h d m uq de an; be reacteiwith a 2,894,007 Patented July 7, 9

95,115-oxido steroid in aqueous media to produce the corresponding 9u-fluoro steroid. Surprisingly enough, this modification of the heretofore used process results in the formation of the desired 9a-fluoro steroids in a yield equal to that obtained according to the prior art anhydrous method.

In one embodiment of the invention the aqueous process is carried out in the presence of an inert nonoxidizing strong acid to increase the rate of reaction. By inert non-oxidizing strong acid is meant an acid which does not react with the starting material and is non-oxidizing under the condition of the reaction. The preferred acids are 2,4-dinitrobenzene sulfonic acid and perchloric acid. Other acids can be used, however, of which sulfuric acid, methanesulfonic acid, ethanesulfonic acid, n-propane -1-sulfonic acid, n-butane-l-sulfonic acid, n-pentanel-sulfonic, n-hexane-l-sulfonic acid, p-nitrobenzenesultonic acid, and trichloroacetic acid are typical examples.

The acid is preferably present in about one-half to thirty moles per mole of the steroid.

As a starting material in the improved process any'o the 95,115-oxido steroids may be utilized. The 95,115-

oxido pregnanes, pregnenes, and androstanes and androstenes are particularly suitable for conversion in this process. Varied substituents can be present in the molecule, such as keto groups at the 3 and/ or 20 positions; hydroxy groups at the 3, 4, 6, 12, 17, and/or 21 positions; and ester groups in the 3, 4, 6, 12, 17, and/or 21 positions. The ester groups are preferably derived from organic carbocyclic acids, especially such acids containing from one to eight carbon atoms inclusive. Among such acids are formic, propionic, butyric, valeric, hexanoic, heptanoic, octanoic, tertiary butylacetic, cyclopentane carboxylic acid, cyclohexane carboxylic acid, benzoic, toluic, phenylacetic, cyclo-pentylpropionic and the like. Typical examples of suitable 95,115-oxido steroids are 95, 1 1-5-oxido-4-pregnene-17u-ol-3-one 95,1 15-oxido-4-pregnene-21-ol-3-one 95, 1 15-oxido-4-pregnene-17a,20a,21-triol-3 -one 95,115-oxido-4-pregnene-17u,205,21-triol-3-one 95,1 15-oxido-4-pregnene-17a-ol-3,20-dione 95,1 15-oxido-4-pregnene-21-o1-3,20-dione 95, 1 15-oxido-4-pregnene-17a,21-diol-3,20-dione 95, 1 l5-oxido-4-pregnene-17a,21-diol-3,2-0-dione ZI-acetate 95,1l5-oxido-4-pregnene-17a,21-diol-3,20-dione 21-propionate 95,115-oxido-4-pregnene-17a,21-dio1-3,20 dione 21-formate 95,115-oxido-4-pregnene-17a,21-diol-3,20-dione 21-butyrate 95,115-oxido-4-pregnene-17a,21-diol-3,20 dione 2l-benzoate 95,115-oxido-4-pregnene-17a,2l-diol 3,20-dione 21-t-butylacetate 95, 1 15-oxido-4-pregnene-17a,21-diol-3 ,20-dione 2 1 -hemisuccinate 95,115-oxido-4-pregnene-17u,21 diol 3,20 dione 21- phenylacetate 95,115-oxido-4-pregnene 3,6-dione 95,1 15-oxido4-pregnene 3,6,20-trione 95,1 15-oxido4-pregnene 17 m-o1-3,6,20-trione 95,115-oxido-4-pregnene 17a,21-diol-3,6,2'0-trione 95, l 15-oxido-4-pregnene 21-ol-3,6,20-trione 95, 1 15-oxido-4-pregnene 6a-ol-3 ,ZO-dione 95,1 1 5-oxido-4-pregnene 65-01-3 ,20-dione 95,115-oxido-4-pregnene 4ol-3 ,ZO-dione 95, 1 15-oxido-4-pregnene 4,17u-diol-3,20-dione 95,115-oxido-4-pregnene 4,170z,21-t1'i0l-3,20 dione 95,115-oxido-4-pregnene 17a,21-diol-3,6,20-trione 21-acetate 95,115-oxido-4-pregnene 6a-ol-3,20-dione'6a-acetate- 3 9,8,llfl-oxido-4-pregnene 4,17a,21-trio1-3,20-dione 4,21-

diacetate 95,1 lp-oxido pregnane-17u,21-diol-3 ,20-dione 21-acetate 9,8,115-oxido pregnane 17a-ol-3,20:dione gmllfi-oxidopregnane 2l-ol-3,20-dione 95,11j8-oxido pregnane 2 l-ol-3 ,20-dione 2 l-acetate 9,9;1 lB-"oxido pregnane 17a,21-dlOl-3,20-d10116 "93,1 lfl-o'xido androstane-3 ,17-dione "918,11fl-oxido androstane-17-ol-3-one 95,1 1 fi-oxido'4-androstene-3 ,17-dione 9,8,1 143-oxido-4-androstene-l7-ol-3-one Thereaction can be carried out in a two-phase system, -i. e.when the organic solvent is a water-immiscible solvent .such as chloroform or in a one-phase system, i.e. when the organic solvent is a water-miscible solvent such as tei hydrofuran. Other water-immiscible solvent media can be used, such as ethylene dichloride, carbon tctra chloride and methylene chloride. "Other water miscible solvents can be used such as dioxane, propionic acid, .butyric acid and acetic acid or the like which are inert to the reactants. The reaction temperature is preferably about C., but a wide range of temperatures can be used such as from 30 C. to +60 C. At a temperature 'of approximately 0 C. the reaction requires from one- ,quarter to four hours for completion. The conditions .will, of course, vary depending on the particular reactants. The hydrogen fluoride is preferably used in excess of the theoretical amount required and usually at least about fifty to'three hundred times the theoretical amount.

The .9ot-fluoro steroid may be conveniently recovered by 'diluting the reaction mixture with water, extracting withan organic solvent such as chloroform, followed by crystallization of the isolated organic material from or- ..ganic solvents such as benzene, acetone, mixtures of benzene-chloroform, acetone-petroleum ether, acetoneether, and ethylacetate ether. Another suitable method is by acylating the crude reaction product and either recovering the product by recrystallization from a solvent, such as a chloroform and benzene mixture or subjecting the acylated mixture to a chromatographic separation on neutral absorbents such-as neutral alumina, Florisil (an adsorbent prepared according to U.S. Patent No. 2,393,625), and activated carbon.

The following examples are given for the purpose of V illustration:

EXAMPLE 1 9a fluoro 1 pregnene 1 15,1 711,2] trial 3,20 dione 21 acetate A one millimole (0.402 g.) sample of 95,11B-oxido-4- pregnene-17a,21-diol-3,20-dione 21-acetate in 10 ml. of chloroform at approximately 0 to 5 C. is treated with a .rnixture of 5 ml. of a 52-55% solution-of hydrogen fluoride (130 rnillimoles) and 5 ml. of 60% perchloric acid (30 millimoles) at 0-5 C. The reaction mixture is stirred and the temperature maintained at 0 C. for a pc- -riodof 15 minutes. At the end ofthis time '50 ml. of water is added and the organic material extracted with several portions of chloroform. The combined chloroform extracts are washed with water until neutral, filtered through anhydrous magnesium sulfate, and the solvent removed in vacuo to afford the crude reaction mixture containing the desired 9a-fluoro-4-pregnene-1'1B,17,21- triol-3,20-dione 21-acetate.

EXAMPLE 2 9a flaoro 4 pregnene 115,17a, 2] triol -.3,20 -di0ne 21 acetate A one millimole sample of 9 9,1 1,8-oxido-4-pregne'nel7a,2l-diol-3,20-dione 2-1-acetate in 10ml. of chloroform at approximately 0 to 5 C. is treated with a mixture of 9 ml. of a 52-55% solution of hydrogenflubride (234 millimoles) and one ml. of 60% perchloric acid (6 millimoles)-at 0.-5..C. Ihe reaction is worked up as @described in Example 1. On the basis of paper strip chro- EXAMPLE 3 9a fluoro 4 pregnene 115,] 711,21 trial 3,20 dione 21 acetate A one millimole sample of 95,11,3-oxido-4-pregnene- 17a,21-di0l-3,20-,di011 ZI-acetate in 10 ml. of chloroform at approximately 0 to 5 C. is treated with a mixture of 9.5 ml. of a 5255% solution of hydrogen fluoride (247 rnillimoles) and 0.5 ml. of 60% perchloric acid (3 millimoles) -at 04 C. The reaction mixture is stirred and the temperature is maintained at 0 C. for a period of 15 minutes. The reaction is worked up as described in Example I. On the basis of paper strip chromatographic analysis of the product, it contains an estimated ca. 60% of the desired compound.

EXAMPLE 4 9a fluoro 4 pregnene 1IB,17a,2I triol 3,20 dione 21 acetate A one millimole sample of 9,8,11fi-oxido-4-pregnene- 17a,-2l'.d1013,20-dl0116 2l-acetate in 10 ml. of chloroform at approximately 0 to 5' C. is treated with a mixture of 9.75 ml. of a 52-55% solution'of hydrogen fluoride (2S3 EXAMPLE 5 9oz fluoro 4 pregnene 11fi,17a,21 triol 3,20 dione 21 acetate A 0.5 millimole sample of 9p,11 8-oxido-4-pregnene- 17a,21-diol-3,20-dione 21-acetate in 5 ml. of chloroform at 0-5" C. is treated with 5 ml. of a 52-55% solution of hydrogen fluoride at approximately 0 to 5 C. The mixture is stirred and the temperature is allowed to rise to and maintained at 25-30 C. for one hour. The reaction is worked up as described in Example 1. On the basis of paper strip chromatographic analysis of the product, it contains an 'estimated'ca. 65% of the desired compound.

EXAMPLE 6 9a fluoro 4 pregnene 11,8,17a,21 triol 3,20 dione 21 acetate A one millimole sample of 9fi,11/8-oxido-4-pregnene- 17a,2-1-diol-3,20-dione 21-acetate in 10 ml. of chloroform at approximately 0 to 5 C. is treated with a mixture of 9.0 ml. of -a -52-55% solution of hydrogen fluoride and 1.81 grams of 2,4-dinitrobenzene sulfonic acid trihydrate (6 millimoles) at 0-5 andthe temperature is maintained at 0 C. for a period of C. The reaction mixture is stirred 15 minutes. The reaction is worked up as described in "Example l. 0n the basis ofpaper strip chromatographic analys s of the-product,itcontains an estimated ca. 65 of the desired compound.

EXAMPLE 7 9aflu0r0-4-pregnene-1 1 48,1 7a,21 -triol-3,20-dione 21 acetate A one millimole sample of 9fi,11,B-oxido-'4-pregncne- 17a,21-diol-3,-20-'dione 2l-acetate in 30 ml. of tetrahydroturn at approximately 0 to 5 C. is treated with a mixture'of 28 ml. o'f'a 52-55% solution of hydrogen fluoride and 2 ml. of-60 perchloric acid at 0-5 C. The reaction mixture is stirred and the temperature is maintained The reaction is worked up a's descn ed in Example 1. On the basis of hydrogen fluoride.

5 paper, strip chromatographic analysis of the product, it contains an estimated ca. 55% of the desired compound.

' EXAMPLE 8 9a-flu0r0-4-pregnene-1113,17a,21-triol3,20-dione 21 -acetate compound.

EXAMPLE 9 9a-flu0r0-4-pregnene-1 1 13,1 7a,21-tri0l-3,20-dione 21-acetate A 25.0 millimole sample. of 95,11 8-oxido-4-pregnene- 17ot,21-diol-3,20-dione 21-acetate in 250 ml. of chloroform at 05 C. is treated with a mixture of 237.5 ml. of a 52-55% solution of hydrogen fluoride and 12.5 ml. of

60% perchloric acid at O to 5 C. The reaction mixture is stirred and the temperature is maintained at C. for a period of 15'minutes. The reaction is worked up as described in Example 1. On the basis of paper strip chromatographic analysis of the product it contains an estimated ca. 55% of the desired compound.

This product is acetylated by treating with 27 ml. of pyridine and 27 ml. of acetic anhydride at 60-65 C. for one hour and five minutes. The excess pyridine and acetic anhydride are removed in vacuo. and the residue dissolved in 100 ml. of chloroform. This solution is washed with water, with. 2.5 N aqueous hydrochloric acid until the washings are acidic, again with water, then with aqueous sodium bicarbonate until the washings are basic, then with water. After filtration of the washed chloroform solution through anhydrous magnesium sulfate, the solvent is removed in vacuo to alford 11.13 g. of crude product. This material is chromatographed over neutral alumina and the portions shown to be the desired product by paper strip analysis are combined, weight=4.81 g. of substantially pure 9a-fluoro- 4-pregnene-1 1 8, 17a,2 1-trio1-3,20-dione 21-acetate.

EXAMPLE 10 9a-fluoro4-pregnene-115J7a,21-tri0l-3,20-di0ne 21 -acetate A 12.5 millimole sample of 9,6,11/8-oxido-4-pregnene- 17a,21-diol-3,20-dione 21-acetate in 125 ml. of chloroform at approximately 0 to 5 C. is treated with a mixture of 118.75 ml. of a 52-55% solution of hydrogen fluoride and 6.25 ml. of 60% perchloric acid at 0-5 C. The reaction mixture is stirred and the temperature is maintained at 0 C. for a period of minutes. The reaction is worked up as described in Example 1. On the basis of paper strip chromatographic analysis of the product it contains an estimated ca. 65% of the desired compound.

The crude product is treated with acetic anhydride and pyridine as described in Example 9. After removal of the excess acylating agent in vacuo, the residue is crystallized twice from acetone-petroleum ether (B.P. 60-70 C.) to afford 2.08 g. of substantially pure 9afluoro-4-pregnene-l 118, l7a,21-triol-3,20-dione 21-acetate.

EXAMPLE l1 9u-flu0r0-4-pregnene-11fiJ7a,21-triol-3,20-dione 21 -acetate A 12.5 millimole sample of 9/3,11,8-oxido-4-pregnene- 17a,21-diol-3,20-dione 2l-acetate in 125 ml. of ice-cold chloroform is treated with an ice-cold mixture of 118.75 ml. of a 52-55% solution of hydrogen fluoride and 6.25 ml. of 60% perchloric acid. The reaction mixture is .ample 1. product indicates that it contains ca. 60% of the desired stirred and the temperature maintained at 0 C. for 25 minutes. The reaction is worked up as described in Ex- Paper Strip chromatographic analysis of the 0 9a flu0r0-4-pregnene 11/3,17a,21 trial-3,20-di0ne 21- acetate A 20.0 millimole sample of 95,11,8-oxido-4-pregnenel7a,21-diol-3,20-dione 2.1-acetate in 200 m1. of ice-cold "chloroform is treated with an ice-cold mixture of 195 ml. of a 52-55% solution of hydrogen fluoride and 5 ml. of

60% perchloric acid. The reaction mixture is stirred and the temperature maintained at 0 C. for 25 minutes. The

' reaction mixture is worked up as described in Example 1.

Paper strip chromatographic analysis of the product indicates that it contains ca. 60% of the desired compound.

The. crude productv is acetylated as described in Example 9. This crude product is crystallized once from chloroform-benzene to give'3.69 g. of substantially pure 9ot-fluoro-4-pregnene-11,8,17a,21-triol-3,20 dione 2l-acetate as the /2 mole benzene solvate.

EXAMPLE 13 11;3,17a,21 trial-3,20-di0ne 21- acetate A 10.0 millimole sample of 95,11/3-oxido-4-pregnene- 17u,21-diol-3,20-dione 21-acetate in 300 m1. of ice-cold tetrahydrofuran is treated with an ice-cold mixture of 295 ml. of a 52-55% solution of hydrogen fluoride and 5.0 ml. of 60% perchloric acid. The reaction mixture is stirred and the temperature maintained at 0 C. for 45 minutes. The reaction mixture is worked up as described in Example 1. Paper strip chromatographic analysis of the product indicates that it contains ca. 65 of the desired compound.

The crude product is acetylated as described in Example 9. This crude acetylated product is crystallized once from chloroform-benzene and once from acetonepetroleum ether (B.P. 60-70 C.) to afford 1.71 g. of substantially pure 9a-fluoro-4-pregnene-1lfl, 17a,21-triol-3, 20-dione 21-acetate.

EXAMPLE 14 z-flu0r0 4 pregnene 115,1 70:,21 trial-3,20-di0ne 21- acetate A 2.5 millimole sample of 9fl,11 8-oxido-4-pregnene- 17u,21-diol-3,20-dione 21-acetate dissolved in 25 ml. of glacial acetic acid is treated with 25 ml. of 52-55% aqueous hydrofluoric acid and the resulting solution allowed to stand at 25-30 C. for 30 minutes. The orangeyellow solution is then poured into ml. of ice water and stored at 0 to 5 C. for one hour. The yellow crystalline product is filtered, washed with water, and dried to yield 0.54 g. of crude 9a-fluorohydrocortisone acetate, M.P. 210-223 C. Recrystallization from acetone gave product melting at 224-229 C. which is identical by mixed melting point and infrared analysis to authentic material.

EXAMPLE 15 9rx-flu0r0 4 pregnene 11/3,17oz,21 trial-3,20-di0ne 21 acetate A 10.0 millimole sample of 95,11,8-oxid0-4-pregnene- 17a,21-diol-3,20-dione in 100 ml. of ice-cold chloroform is treated with an ice-cold mixture of 90 ml. of a 5255% solution of hydrogen fluoride and 10 ml. of 60% perchloric acid. The reaction mixture is stirred and the temperature is maintained at C. for 15 minutes. The reaction is worked up as described in Example 1. The crude product is acetylated as described in Example 9.

This crude acetylated product is crystallized from chloroform-benzene to afford 1.59. g. of substantially pure 9afiuoro-4-pregnene-1'15,17a,21triol-3,20-dione 21 acetate as the /2 mole benzene s'olvate.

EXAMPLE 16 9a-fluoro-4-pregnene-11fl,21-di0l-3,20-di0ne 21-aceta'te 9a-fluor0-4-pregnene-1118,17a-diol-3,20-dione A 3.445 g. sampleof 95,1'1B-oxido-4-pregnene-17a-ol- 3,20-dione in 300 ml. of tetrahydrofuran at 0-5 C. is treated with 300 ml. of a 52-55% solution of hydrogen fluoride at 0 to C. The reaction mixture is stirred, allowed to warm to room temperature and the temperature maintained at 2530 C. for one half hour. The reaction is worked up as described in Example 1. The crude product is treated wit h acetic anhydride and pyridineas described infExample 9. This crude acetylated product is chromatographed over 148 g. of neutral alumina and the portions/shown to contain the desired 8 9u-fluoro-4-pregnene-1 15, 171: -'dio1- 3,20 -.dione by;paper chromatographic analysis are combined. Recrystallization from acetone aflords the substantially pure product.

What is claimed is:

1. In the process'wherein hydrogen fluoride is reacted with a 9fl,11 8-oxido-steroid to produce the corresponding 9aefluorol1-fl hydroxy-steroid, the improvement which comprises carrying out thereaction inan aqueous solvent medium and in the presence of .a non-oxidizing acid -selectedfrom the group consisting of perchloric acid, sulfuric acid, trichloro'acetic acid, the lower alkanesulfonic acids p-nitrobenzenesulfonic acid and 2-4 dinitrobenzene- .sulfonic acid.

2. In the process wherein hydrogen fluoride is reacted with a 9B,1lp-oxido-4-pregnene compound to produce the corresponding 9u-fluorol1B-hydroxy-4-pregnene, the improvement which comprises carrying out the reaction in an aqueous solvent medium in the presence of perchloric acid.

3. .In the process wherein hydro'gen fluoride is reacted with a 913,1 1p-oxido-4-pregnene compound to produce the corresponding 9a-fluoro-11-fl hydroxy-4-pregnene, the improvement which comprises carrying out the reaction in an aqueous solvent medium in the presence of 2,4-dinitrobenzene sulfonic acid.

4. A'process which comprises reacting 95,115-oxido-4- pregnene-l7a,2l-diol-3,20-dione 21-acetate with aqueous hydrogen fluoride at approximately 0 to 5 C. in the presence of a mixture of chloroform and-perchloric acid to produce 9a-fiuoro-4-pregnene --1 l 8,l7u,21 triol 3,20- dione 21-acetate.

References Cited in the file of this patent Fried: Jour. Am. Chem. Soc. 75, 2273-74 (1953'). Fried: Jour. Am. Chem. Soc. 76, 1455 (1954). 

1. IN THE PROCESS WHEREIN HYDROGEN FLOURIDE IS REACTED WITH A 9B, 11B-OXIDE-STERIOD TO PRODUCE THE CORRESPONDING 9A-FLUORO-11BHYDROXY-STEROID, THE IMPROVEMENT WHICH COMPRISES CARRYING OUT THE REACTION IN AN AQUEOUS SOLVENT MEDIUM AND IN THE PRESENCE OF A NON-OXIDIZING ACID SELECTED FROM THE GROUP CONSISTING OF PERCHLORIC ACID, SULFURIC ACID, TRICHLORACETIC ACID, THE LOWER ALKANESULFONIC ACIDS P-NITROBENZENESULFONIC ACID AND 2-4 DINITROB ENZENESULFONIC ACID.
 4. A PROCESS WHICH COMPRISES REACTING 9B,11B-OXIDO-4PREGENE 17A,21-DIOL-3,20-DIONE 21-ACETATER WITH AQUEOUS HYDROGEN FLUORIDE AT APPROXIMATELY 0* TO 5*C. IN THE PRESENCE OF A MIXTURE OF CHLOROFORM AND PERCHLORIC ACID TO PRODUCE 9AFLUORO-4-PREGENE - 11B, 17A 21- TRIOL- 3,20DIONE 21-ACETATE. 